title: The TPO/c-MPL pathway in the bone marrow may protect leukemia cells from chemotherapy in AML Patients.
abstract: Accumulating evidence indicates that the interaction of human LSCs (leukemic stem cells) with the hematopoietic microenvironment, mediated by the thrombopoietin (TPO)/c-MPL pathway, may be an underlying mechanism for resistance to cell cycle-dependent cytotoxic chemotherapy. However, the role of TPO/c-MPL signaling in AML (acute myelogenous leukemia) chemotherapy resistance hasn't been fully understood. The c-MPL and TPO levels in different AML samples were measured by flow cytometry and ELISA. We also assessed the TPO levels in the osteoblasts derived from bone mesenchymal stem cells (BMSCs). The survival rate of an AML cell line that had been co-cultured with different BMSC-derived osteoblasts was measured to determine the IC50 of an AML chemotherapy drug daunorubicin (DNR). The levels of TPO/c-MPL in the initial and relapse AML patients were significantly higher than that in the control (P < 0.05). The osteoblasts derived from AML patients' BMSCs secreted more TPO than the osteoblasts derived from normal control BMSCs (P < 0.05). A strong positive correlation between the TPO level and c-MPL expression was found in the bone marrow mononuclear cells of the relapse AML patients. More importantly, the IC50 of DNR in the HEL + AML-derived osteoblasts was the highest among all co-culture systems. High level of TPO/c-MPL signaling may protect LSCs from chemotherapy in AML. The effects of inhibition of the TPO/c-MPL pathway on enhancing the chemotherapy sensitivity of AML cells, and on their downstream effector molecules that direct the interactions between patient-derived blasts and leukemia repopulating cells need to be further studied.
authors.affiliation: Department of Hematology, Xinqiao Hospital, Third Military Medical University, Chongqing, 400037, People's Republic of China.
authors.forename: Zeng
authors.initials: Z
authors.lastname: Dong-Feng
authors.forename: Liu
authors.initials: L
authors.lastname: Ting
authors.forename: Zhang
authors.initials: Z
authors.lastname: Yong
authors.forename: Chang
authors.initials: C
authors.lastname: Cheng
authors.forename: Zhang
authors.initials: Z
authors.lastname: Xi
authors.forename: Kong
authors.initials: K
authors.lastname: Pei-Yan
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D001324:Autoantigens / Q000378:metabolism*; D001853:Bone Marrow / Q000378:metabolism*; D016022:Case-Control Studies; D002453:Cell Cycle / Q000502:physiology; D002460:Cell Line; D002648:Child; D018920:Coculture Techniques; D005260:Female; D006801:Humans; D007453:Iodide Peroxidase / Q000378:metabolism*; D033862:Iron-Binding Proteins / Q000378:metabolism*; D015470:Leukemia, Myeloid, Acute / Q000378:metabolism* / Q000401:mortality*; D008297:Male; D008875:Middle Aged; D010006:Osteoblasts / Q000378:metabolism; D053628:Receptors, Thrombopoietin / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology; D013234:Stem Cells / Q000378:metabolism; D015996:Survival Rate; D055815:Young Adult
chemical_list: D001324:Autoantigens; D033862:Iron-Binding Proteins; D053628:Receptors, Thrombopoietin; C082218:MPL protein, human; C056658:TPO protein, human; D007453:Iodide Peroxidase